Various fluorinating agents have been developed in order to obtain fluoro-compounds by fluorinating various compounds. Examples of fluorinating agents include fluorine gas, hydrogen fluoride, tetra-alkyl fluorides, alkali metal fluorides and hydrofluoric acid/pyridine. Nucleophilic fluorinating agents, such as diethylaminosulfur trifluoride (DAST), N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (also known as Ishikawa's reagent) and N-(2-chloro-1,1,2-trifluoroethyl)diethylamine (also known as Yarovenko's reagent), are particularly effective in fluorinating hydroxyl groups and are thus widely used in studies.
Fluoro-compounds such as fluoroproline derivatives of hydroxyproline are highly useful intermediates in the production of pharmaceutical and agrochemical products.
For example, Patent Document 1 describes that fluoropyrrolidine derivatives derived from fluoroproline derivatives act as effective DPP-IV inhibitors and are useful in the treatment of diabetes, immune deficiencies, skin diseases and prostatomegaly.
DAST has several drawbacks wherein SF4 used in the production of DAST is highly toxic and harmful, and DAST is too costly to be used in industrial applications. Furthermore, DAST is unstable at room temperature and generates explosive materials, so that storage and use of the material need to be strictly regulated. These drawbacks make DAST unsuitable for use in industrial-scale fluorination.
α,α-difluoroalkylamine fluorinating agents such as Ishikawa's reagent and Yarovenko's reagent are less costly and are considered more suitable for fluorinating hydroxyl groups than DAST.
However, the production of α,α-difluoroalkylamine fluorinating agents results in the formation of considerable amounts of by-products that must be removed by distillation so that the agents can be used in fluorination processes (Non-Patent Documents 1 through 3).
Though α,α-difluoroalkylamine fluorinating agents are more stable than DAST, distilling these agents on an industrial scale is a task of considerable difficulty.
To avoid the cumbersome distillation process, the present inventors used N-(2-chloro-1,1,2-trifluoroethyl)diethylamine, one of α,α-difluoroalkylamine fluorinating agents, in fluorinating different alcohol derivatives without distillation. However, this attempt led to the formation of chlorinated by-products in large amounts. These chlorinated products have boiling points and melting points similar to those of the desired fluorinated product and separating them required a substantial effort.
Patent Document 1 International Publication No. WO02/38541 Pamphlet
Non-Patent Document 1 Bull. Chem. Soc. Jpn, 52(11), 3377 (1979)
Non-Patent Document 2 Zh. Obshch. Khim., 29, 2159 (1959)
Non-Patent Document 3 Org. React., 21, 158 (1974)